Abstract
Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans. In yeast, Rad52 is important for most HR events; Rad52 mutations disrupt repair of DNA double-strand breaks and targeted DNA integration. Surprisingly, in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. However, recent work demonstrated that mutations in human RAD52 are synthetically lethal with mutations in several other HR proteins including BRCA1 and BRCA2. These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. In this review, we focus on the Rad52 activities and functions in HR and the possibility of using human RAD52 as therapeutic target in BRCA1 and BRCA2-deficient familial breast cancer and ovarian cancer.
Highlights
Homologous recombination (HR) is a highly conserved pathway that plays a major role in repair of double-strand breaks (DSBs), the most harmful type of DNA damage, which are induced by ionizing radiation (IR), chemical agents or during repair of stalled replication forks and incomplete telomere synthesis
Tails, formation of Rad51-ssDNA filaments that search for homology and promote strand invasion into the homologous duplex DNA-template leading to the formation of a displacement loop (D-loop) intermediate, which provide a template for DNA polymerase to extend the invading DNA strand
In the canonical DNA double-strand break repair mechanism (DSBR), the displaced strand of the D-loop may anneal with the second resected end of the DSB leading to formation of double D-loops that are converted to Holliday junctions
Summary
Homologous recombination (HR) is a highly conserved pathway that plays a major role in repair of double-strand breaks (DSBs), the most harmful type of DNA damage, which are induced by ionizing radiation (IR), chemical agents or during repair of stalled replication forks and incomplete telomere synthesis. In the canonical DNA double-strand break repair mechanism (DSBR), the displaced strand of the D-loop may anneal with the second resected end of the DSB leading to formation of double D-loops that are converted to Holliday junctions. Single‐end DSBs are formed; for instance, during replication fork collapse It was cells crossing over may lead to excessive loss of heterozygosity. These data indicate a complex organization of the HR machinery in mammalian cells and suggest that RAD52 may play a back-up role, when an alternative HR mechanism(s) that depends on BRCAs and several other HR proteins are unavailable It is to note, that in contrast to many other eukaryotes S. cerevisiae genome does not encode BRCA1 and BRCA2 homologs suggesting that Rad may perform their functions in yeast. More comprehensive information on human RAD52 and its yeast ortholog may be found in a number of excellent previous reviews [1,9,14,21,22]
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